In a breakthrough for the buzzing world of CRISPR research, a team of scientists has demonstrated a use of the gene editing tool to treat a genetic disease in mice before they are born.
The proof-of-concept study brings them one step closer — though still miles away — to the ultimate goal of treating severe human diseases diagnosed early in pregnancy, according to the researchers from Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania.
“A significant amount of work needs to be done before prenatal gene editing can be translated to the clinic,” said study co-leader William Peranteau, a pediatric and fetal surgeon in CHOP’s Center for Fetal Diagnosis and Treatment. “Nonetheless, we are excited about the potential of this approach to treat genetic diseases of the liver and other organs for which few therapeutic options exist.”
For their study, published in Nature Medicine, the team combined two different techniques: Using the well-known CRISPR-Cas9 compound as a guide, they fused an enzyme to it that chemically modifies the genetic code once the compound arrived at the specified genetic location. Dubbed base editor 3, this method is described as potentially safer than the cut-and-paste model of regular CRISPR-Cas9, which researchers have warned could cause off-target effects.
But before they tested the tool on a group of mice engineered to develop the lethal liver disease hereditary tyrosinemia type 1 (HT1), the investigators first tried it out with the PCSK9 gene — a cholesterol regulator now targeted by a new class of cardio drugs — and showed that the fetuses receiving this treatment were born with significantly lower cholesterol levels.
Similarly, the intended effect was observed in newborn mice which had a related gene — not the disease-causing one — disabled in utero: They “carried stable amounts of edited liver cells for up to three months after the prenatal treatment, with no evidence of unwanted, off-target editing at other DNA sites” with “improved liver function and preserved survival.”
In fact, they did even better than mice born with HT1 that are subsequently treatment with nitisinone and diet, the current standard of care for infants with HT1.
The investigators remain cautiously optimistic about their early work, already testing alternative delivery systems to the adenovirus vectors used in this experiment, as it’s been suggested that adenovirus vectors, a mainstay in gene therapy experiments, may cause adverse responses from the host’s immune system. Other directions of research include directly editing disease-causing genes and exploring the tech’s application in other organs.
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